The Role of Mutation and Epimutation in the Development of Human Disease

Abstract

The paradigm of disease causation holds that disease represents the manifestation or several manifestations of an underlying process that has one or more root causes. Thus, human diseases reflect a spectrum of pathologies and mechanisms of disease pathogenesis. The general categories of disease affecting humans include (a) hereditary diseases, (b) infectious diseases, (c) inflammatory diseases, and (d) neoplastic diseases. Pathological conditions representing each of these general categories have been described for every tissue in the body. Despite the grouping of diseases by the common features of the general disease type, the pathogenesis of each of the various diseases is unique, and in some cases multiple mechanisms can give rise to a similar pathology (disease manifestation). Disease causation may be related to intrinsic factors or extrinsic factors, but many or most diseases are multifactorial, involving a combination of intrinsic and extrinsic factors. It is now well recognized that most major diseases are ultimately the result of aberrant gene expression and that susceptibility to disease is significantly influenced by patterns of gene expression in target cells or tissues for a particular type of pathology. It follows that gene mutations and other genetic alterations are important in the pathogenesis of many human diseases. Similarly, nongenetic alterations affecting the expression of key genes, called epimutations, may also contribute to the genesis of disease at many tissue sites. In this chapter, general concepts related to the molecular basis for the major disease types are reviewed. This review is not intended to be comprehensive. Rather, the current state of understanding related to the genes and molecular mechanisms (genetic and epigenetic) that contribute to illustrative diseases is described.